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A New Class of Antibiotics: Natural Inhibitors of Bacterial Cytoskeletal Protein FtsZ to Fight Drug-susceptible and Multi-drug R

Posted Jun 20 2010 5:00pm

Description of Invention:
The risk of infectious diseases epidemic has been alarming in recent decades. This is not only because of the increase incident of so-called "super bugs", but also because of the scarce number of potential antibiotics in the pipeline. Currently, the need for new antibiotics is greater than ever! The present invention by the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), part of the National Institute of Health (NIH), address this urgent need. The invention is a new class of chrysophaentin antibiotics that inhibit the growth of broad-spectrum, drug-susceptible, and drug-resistant bacteria.

Derived from the yellow algae Chrysophaeum taylori, the inventor has extracted 8 small molecules of natural products and tested for antimicrobial activity against drug resistant bacteria, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE), as well as other drug susceptible strains. Structurally, the molecules represent a new class of antibiotic that also likely work through a distinct mechanism of action from that of current antibiotics, which is key for the further development of antibiotics that inhibit drug-resistant strains.

The bacterial cytoskeletal protein FtsZ is a GTP-ase and has structural homology to the eukaryotic cytoskeletal protein tubulin, but lacks significant sequence similarity. FtsZ is essential for bacterial cell division. It is responsible for Z-ring assembly in bacteria, which leads to bacterial cell division. Experiments show that the disclosed compounds are competitive inhibitors of GTP binding to FtsZ, and must bind in the GTP-binding site of FtsZ. Inhibition of FtsZ stops bacterial cell division and is a validated target for new antimicrobials. FtsZ is highly conserved among all bacteria, making it a very attractive antimicrobial target.

  • Therapeutic potential for curing bacterial infections in vivo, including for clinical and veterinary applications.
  • Antiseptics in hospital settings.
  • Since FtsZ is structurally similar, but do not share sequence homology to eukaryotic cytoskeletal protein tubulin, these compounds may have antitumor properties against some cancer types or cell lines.

  • Structurally distinct antimicrobial compounds.
  • Attack newly validated antibacterial targeted protein FtsZ.
  • These compounds have a unique mechanism of action which inhibit FtsZ by inhibiting FtsZ GTPase activity.
  • Inhibit drug-susceptible and drug-resistant bacteria.

Development Status:
  • Initial isolation and chemical structural characterization using NMR spectroscopy have been conducted.
  • Antimicrobial testing against MRSA, Enterococcus faecium, and VRE were conducted in vitro using a modified disk diffusion assay and microbroth liquid dilution assays.
  • MIC50 values were determined using a microbroth dilution assay.
  • Mode of action was elucidated and Saturation Transfer Difference (STD) NMR was conducted to map the binding epitope of one of these compounds in complex with recombinant FtsZ.
  • Other experiments on different areas to further characterize these compounds and their mode of action are currently on going.

Carole A Bewley Clore (NIDDK)

Patent Status:
HHS, Reference No. E-116-2010/0
US, Application No. 61/308,911 filed 27 Feb 2010

Relevant Publication:
  1. DJ Haydon et al. An inhibitor of FtsZ with potent and selective anti-staphylococcal activity. Science. 2008 Sept 19; 321(5896):1673-1675. [ PubMed: 18801997 ]
  2. NR Stokes et al. Novel inhibitors of bacterial cytokinesis identified by a cell-based antibiotic screening assay. J Biol Chem. 2005 Dec 2; 280(48):39709-39715. [ PubMed: 16174771 ]
  3. J Wang et al. Discovery of small molecule that inhibits cell division by blocking FtsZ, a novel therapeutic target of antibiotics. J Biol Chem. 2003 Nov 7; 278(45):44424-44428. [ PubMed: 12952956 ]
  4. P Domadia et al. Berberine targets assembly of Escherichia coli cell division protein FtsZ. Biochemistry. 2008 Mar 11; 47(10):3225-3234. [ PubMed: 18275156 ]
  5. P Domadia et al. Inhibition of bacterial cell division protein FtsZ by cinamaldehyde. Biochem Pharmacol. 2007 Sep 15:74(6):831-840. [ PubMed: 17662960 ]
  6. S Urgaonkar et al. Synthesis of antimicrobial natural products targeting FtsZ: (+/-)-dichamanetin and (+/-)-2'''-hydroxy-5''-benzylisouvarinol-B. Org Lett. 2005 Dec 8;7(25):5609-5612. [ PubMed: 16321003 ]

Licensing Status:
Available for licensing.

Collaborative Research Opportunity:
The National Institute of Diabetes and Digestive and Kidney Diseases, Laboratory of Bioorganic Chemistry is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the chrysophaentin antibiotics. Please contact Cindy K. Fuchs at 301-451-3636 or for more information.

Infectious Diseases
Infectious Diseases - Therapeutics

For Additional Information Please Contact:
John Stansberry Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Phone: 301-435-5236
Fax: 301-402-0220

Ref No: 2123

Updated: 06/2010

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